Role of melatonin in reduction of lipid peroxidation and peroxynitrite formation in non-septic shock induced by zymosan

Zymosan, a non-bacterial agent, causes inflammation by inducing the product ion of a variety of cytokines and pro-inflammatory mediators, wherein react ive oxygen species including nitric oxide and peroxynitrite are known to pl ay a crucial role in the inflammatory process. The current study was design ed to investigate the protective effect of melatonin, a radical scavenger a nd antioxidant, on non-septic shock induced by zymosan in the rat. Four gro ups of rats (controls, melatonin-injected [5 mg/kg x 6], zymosan-injected [ 500 mg/kg], and zymosan + melatonin) were used in this experiment. Thiobarb ituric acid reactive substances (malondialdehyde [MDA] + 4-hydroxyalkenais [4-HDA]), as an index of lipid peroxidation, were measured in the liver, lu ng, small intestine (ileum), kidney and pancreas. Twenty-four hours after z ymosan administration, MDA + 4-HDA levels were significantly increased in t he liver, lung, small intestine, and kidney while the increase in the pancr eas was not statistically significant compared to levels in control rats. T he percentage increases in lipid peroxidation products were 34.3%, 39.2%, 4 8.5%, 32.5%, and 17.4% for the liver, lung, small intestine, kidney, and pa ncreas, respectively. In animals given melatonin 30 minutes before zymosan, and 5 more times after zymosan (i.e., every 4 hours), the increase in MDA + 4-HDA levels was reduced in all organs studied. There was also a signific ant increase in the volume of peritoneal exudate in zymosan-treated rats th at was reduced when the zymosan-shocked rats received melatonin. After zymo san administration, immunohistochemical and histological examination demons trated a marked increase in the immunoreactivity to nitrotyrosine, a specif ic "footprint" of peroxynitrite, and tissue damage in the liver, lung, and small intestine of zymosan-shocked rats. Again, melatonin treatment reduced both nitrotyrosine immunoreactivity and tissue damage associated with zymo san administration.